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FDA panel calls for warning labels on gadolinium-based contrast agents for MRI

(15.09.2017)


Background:

Gadolinium-based agents are used to enhance the contrast in images produced by MRI scanners. First concerns about gadolinium side effects emerged over a decade ago, after some patients with renal failure developed Nephrogenic Systemic Fibrosis (NSF) and a link was found between the "debilitating" condition and GBCA used in MRIs. 


Photo: Modern 3T MRI scanner


In September 2010, the FDA adopted safety label changes including a contraindication for patients with renal insufficiency. FDA also encouraged healthcare professionals and patients to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program.

Then, in July 2015, the FDA issued a Drug Safety communication that noted reports of retention of gadolinium in the brain after the use of GBCAs, which underscored the increased retention with linear GBCAs compared to macrocyclic GBCAs. In that communication the FDA urged physicians to limit the use of such agents to "clinical circumstances in which the additional information provided by the contrast is necessary," also urging them to reassess the necessity of repetitive contrast MRIs in established treatment protocols.

In May 2017, the FDA reported that a new review showed that gadolinium is retained in brain and other body tissues, but no new adverse events were uncovered. Still, it stated that retention is greater for linear over macrocyclic GBCs and assessments are continuing as to whether reports of NSF in patients with normal kidney function are related to gadolinium retention. Accordingly, the FDA had announced to organize a public meeting to discuss this issue in the future.

Two months later, the European Medicines Agency (EMA) issued a final opinion confirming restrictions on the use of the intravenous linear agents gadoxetic acid and gadobenic acid, as well as gadopentetic acid given intra-articularly. The EMA recommended the suspension of all other linear products.

Public meeting
The announced public meeting took place last Friday, Sept. 8, 2016. During the all-day meeting, the committee heard from representatives of pharmaceutical industry, researchers, patients and patient advocacy groups. The meeting was also broadcasted over the internet.

During the meeting, some representatives of companies producing macrocyclic contrast agents sought to emphasize differences in the chemical structure between their products and linear contrast agents, which may lead to greater retention of linear products; while linear contrast agent manufacturers underscored that retention occurs with both classes, differences in retention are slight, and the threshold for toxicity is unclear.

Although the members of MIDAC overwhelmingly concluded there was not enough evidence to show a causal relationship between adverse symptoms and gadolinium retention, they still expressed their concerns.

"A lack of evidence is not evidence of safety," said Sonia Hernandez-Diaz, MD, Harvard TH Chan School of Public Health, Boston, Massachusetts.

At the end of the day-long meeting, committee members were asked to vote on whether they agreed with the FDA's plan to include a warning for all GBCAs, along with a warning that all or some of the linear versions may have greater retention than macrocyclics in certain organs.

"In spite of the lack of evidence, there is obvious concern in the medical community and industry and patient populations. I think it's important that information be put out there with regard to gadolinium retention," agreed Dr Herscovitch, MD, acting chair of the committee and director of the PET Department at the National Institutes of Health (NIH).

The overwhelming majority voted "yes" to the FDA plan. The lone "no" vote came from Alicia Toledano, ScD, president of Biostatistics Consulting, Kensington, Maryland. She said that the FDA's plan doesn't go far enough.

The one abstaining vote came from Sean Hennessy, PhD, PharmD. "I think the decision of whether or not linear agents should remain available is a risk-benefit decision, but we did not have that decision in a 1-day meeting," he said.

During the postvote discussion, two other committee members suggested, that the EMA proposal would have been another option that unfortunately was not at their deliberation.

Besides the recommendation for warning labels the committee also voted unanimously to recommend the FDA consider requiring industry conduct more research to help the agency determine if regulatory action "including withdrawal of approval and restriction of indicated populations" is necessary.




Related information


FDA: Information on Gadolinium-Based Contrast Agents
FDA: July 27, 2015: FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI)
FDA: MedWatch Online Voluntary Reporting Form

EMA: Gadolinium-containing contrast agents
EMA: July 21, 2017: EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans
EMA: July 7, 2017: PRAC confirms restrictions on the use of linear gadolinium agents
EMA: March 10, 2017: PRAC concludes assessment of gadolinium agents used in body scans and recommends regulatory actions, including suspension for some marketing authorisations
EMA: March 8, 2016: PRAC reviews gadolinium contrast agents used in MRI scans

InsideRadiology: Gadolinium Contrast Medium (MRI Contrast agents)
The Lighthouse Project: Gadolinium Toxicity
MRI Questions: Why are most MR contrast agents based on the element gadolinium? 




Related EVISA News

July 29, 2017: EMA Issues Final Opinion Limiting Gadolinium Contrast Agents in Body Scans

May 23, 2017: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs
March 11, 2017: European Medicines Agency recomments to pull linear Gadolinium-based MRI contrast agents from market
April 10, 2016: New Studies Question Safety of MRI Contrast Agents
August 13, 2015: FDA investigating risk of gadolinium contrast agent brain deposits
March 4, 2015: Detection of Gd-based contrast agent in the skin of a patient eight years after administration
October 29, 2012: Identification and quantification of potential metabolites of Gd-based contrast agents
September 15, 2010: US FDA Announces Gadolinium-Based MRI Contrast Agent Warning
March 25, 2010: Publication on the separation of Gd-based contrast agents awarded
May 4, 2009: Gadolinium speciation analysis in search for the cause of nephrogenic systemic fibrosis (NSF)


last time modified: September 15, 2017









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